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Cyclobutyl dihydroquinoline sulfonamide compounds

a technology of cyclobutyl dihydroquinoline and sulfonamide, which is applied in the field of cyclobutyl dihydroquinoline compounds, can solve the problems of nonselective sodium channel inhibitors, limited dose and use, and anxiety and over excitability

Pending Publication Date: 2022-09-29
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hence, while inhibiting Nav1.1 may provide use for treating pain, it may also be undesirable possibly leading to anxiety and over excitability.
Nonselective sodium channel inhibitors such as lidocaine, mexiletine, and carbamazepine show clinical efficacy in chronic pain, including neuropathic pain, but they are limited in dose and in use, likely due to effects on sodium channels outside the pain pathway.
However, these compounds do not distinguish between the various sodium channel subtypes, making them unsuitable for use as systemic pain killers.

Method used

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  • Cyclobutyl dihydroquinoline sulfonamide compounds
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  • Cyclobutyl dihydroquinoline sulfonamide compounds

Examples

Experimental program
Comparison scheme
Effect test

examples 1 & 2

ert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide and 1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide, Respectively

[0421]

STEP 1: (M)-1-(4-(3-(TERT-BUTYL)CYCLOBUTYL)-5-FLUORO-2-METHOXYPHENYL)-N-(ISOXAZOL-3-YL)-2-OXO-1,2-DIHYDROQUINOLINE-6-SULFONAMIDE

[0422]A vial was charged with palladium(II) acetate (2.7 mg, 0.012 mmol), 2′-(dicyclohexylphosphino)-N2,N2,N6,N6-tetramethyl-[1,1′-biphenyl]-2,6-diamine (10.6 mg, 0.024 mmol), and (M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.202 mmol). (3-(tert-butyl)cyclobutyl)zinc(II) iodide (0.2 M in THF, 2.0 mL, 0.41 mmol) was added and the reaction was stirred for two hours at 50° C. The reaction was then diluted with ethyl acetate and washed twice with 1 N HCl. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated. The ...

example 3

(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

[0424]

[0425]A vial was charged with palladium(II) acetate (7.3 mg, 0.032 mmol) 2′-(dicyclohexylphosphino)-N2,N2,N6,N6-tetramethyl-[1,1′-biphenyl]-2,6-diamine (28 mg, 0.065 mmol), and (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (160 mg, 0.324 mmol). (3-(tert-Butyl)cyclobutyl)zinc(II) iodide (0.2 M in THF, 3.2 mL, 0.65 mmol) was added, and the reaction was stirred for two hours at 50° C. The reaction was then diluted with ethyl acetate and washed twice with 1 N HCl. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g column, gradient elution 0-50% [3:1 EtOAc:EtOH]:heptane) to give (P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (90 mg, ...

example 4

(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

[0426]

STEP 1: (P)-1-(5-FLUORO-2-METHOXY-4-(5,8-DIOXASPIRO[3.4]OCTAN-2-YL)PHENYL)-N-(ISOXAZOL-3-YL)-N-(4-METHOXYBENZYL)-2-OXO-1,2-DIHYDROQUINOLINE-6-SULFONAMIDE

[0427]A vial was charged with (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Intermediate F) (0.500 g, 0.814 mmol), palladium(II) acetate (10.96 mg, 0.049 mmol), and 2′-(dicyclohexylphosphino)-N2,N2,N6,N6-tetramethyl-[1,1′-biphenyl]-2,6-diamine (0.043 g, 0.098 mmol). 5,8-Dioxaspiro[3.4]octan-2-ylzinc(II) bromide (0.1 M in THF, 14 mL, 0.70 mmol) was added and the reaction was stirred at 50° C. for 16 h. The reaction was then diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material w...

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Abstract

The present invention provides a cyclobutyl dihydroquinoline sulfonamide compound of Formula (I), an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, that inhibits voltage-gated sodium channels, in particular Nav1.7. The compounds are useful for the treatment of diseases associated with the activity of sodium channels such as pain disorders, cough, and itch. Also provided are pharmaceutical compositions containing the compounds of the present invention. Also further provided is an atropi-selective preparation of said compounds of Formula (I), and intermediate thereof.

Description

RELATED APPLICATION[0001]This application claims priority from U.S. Provisional Application No. 63 / 037,001, having a filing date of Jun. 10, 2020.FIELD OF THE INVENTION[0002]The present invention provides cyclobutyl dihydroquinoline compounds that are inhibitors of voltage-gated sodium channels (Nav), in particular Nav 1.7, and are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.BACKGROUND OF THE INVENTION[0003]A 2011 report of the institute of medicine estimates that 100 million adults in the US, roughly 30% of the population, suffer from chronic pain (C & E News, Bethany Halford, “Changing the Channel”, published 3-24). Chronic pain by definition involves abnormal electrical spiking of neurons in the pain pathways: peripheral sensory neurons, spinal cord neurons, neurons in the pain matrix of the brain (e.g., somatosensory cortex, insu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D401/12C07D413/12C07D215/36
CPCC07D401/12C07D413/12C07D215/36A61P29/00A61P25/04A61K31/4709A61K31/506A61K31/501A61P11/14A61P17/04
Inventor MILGRAM, BENJAMIN CMARX, ISAAC EWANG, HAOXUANCHERNEY, ALAN H
Owner AMGEN INC
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